One of the striking features of the pathophysiology of the B-cell response in man during aging is the selective increase in the number of B-cells and the gradual loss of regulatory control with an increasing tendency to produce homogeneous immunoglobulin. These are manifested in the aged as different forms of diseases such as autoimmunity, benign monoclonal gammopathy (BMG), Waldenstrom's macroglobulinemia or multiple myeloma. In each instance, expansion of a clone of B-cells has occurred. Although a large body of clinical and experimental data on such cases has been accumulated over the years, very little is known about the etiology, the mechanism and the significance of the different manifestations of immunoglobulin production in aging man. This proposal is designed to re-establish normal host regulation of the B-cell clone in a murine model of Waldenstrom's macroglobulinemia and to investigate the mechanism by which such regulation is implemented. Our working hypothesis is that the expansion of selected clones of B-cells is either due to the inability of the B-cell to respond to regulatory signals or due to the inability to maintain tolerance against the antigen to which the B-cell clone is responding. Specific T-cells responsible for tolerance induction are present but can no longer maintain the proper reduction of the abnormal B-cell clone size under a tolerance inducing, immunosuppressive regimen would create an environment in which the host reassesses self and non-self, recapitulating the B-cell ontogeny from which regulation of the abnormal clone is re-instituted.